Rapid, fur-reaching research advances in preclinical opioid chemistry and pharmacology have generated ample, persuasive data that several well-characterized opioid peptide analogs have potential clinical utility. Advantages suggested from preclinical studies of two such compounds, DPDPE and biphalin, compared to opioids is current clinical use include diminished addiction liability, fewer mu-opioid side effects shci as constipation or urinary retention, and therapeutic efficacy in patients with tolerance to mu-opioid analgestics such as after prior morphine therapy for chronic cancer pain. However, no clinical datanow exist regarding the clinical safety and efficacy of these analgesic peptides, particularly after intrathecal applicaiton although that route is the most appropriate choice for their initial clinical use. Hence, we now request funding for preliminary evaluation of the safety and efficacy of PDDPE and biphalin prior to their initial clinical trials in two clinical pain models, postoperative pain in otherwise healthy patients, and chronic cancer pain in patients with pre-existing intrathecal catheters for morphine delivery. It is our intention, upon successful completion of preclinical toxicologic, kinetic, and distribution studies by our collaborators, to apply for an IND (after a pre-IND meeting at the invitation of the FDA). We shall then seek supplementary funding for Phase 1 and Phase 2 trials in healthy volunteers and patients, respectively. The Phase 2 trials will be prospective, double-blind, randomized and controlled (controls will receive standard analgesics), conducted in our NIH-funded General Clinical Research Center.